De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes.
The pluripotency-determining gene Oct3/4 (also called Pou5f1) undergoes postimplantation silencing in a process mediated by the histone methyltransferase G9a. Microarray analysis now shows that this enzyme may operate as a master regulator that inactivates numerous early-embryonic genes by bringing about heterochromatinization of methylated histone H3K9 and de novo DNA methylation. Genetic studies in differentiating embryonic stem cells demonstrate that a point mutation in the G9a SET domain prevents heterochromatinization but still allows de novo methylation, whereas biochemical and functional studies indicate that G9a itself is capable of bringing about de novo methylation through its ankyrin domain, by recruiting Dnmt3a and Dnmt3b independently of its histone methyltransferase activity. These modifications seem to be programmed for carrying out two separate biological functions: histone methylation blocks target-gene reactivation in the absence of transcriptional repressors, whereas DNA methylation prevents reprogramming to the undifferentiated state.
Epsztejn-Litman
Silvina
S
Departments of Experimental Medicine and Cellular Biochemistry Hebrew University Medical School Ein Kerem Jerusalem, 91120 ISRAEL.
Feldman
Nirit
N
Departments of Experimental Medicine and Cellular Biochemistry Hebrew University Medical School Ein Kerem Jerusalem, 91120 ISRAEL.
Abu-Remaileh
Monther
M
Departments of Experimental Medicine and Cellular Biochemistry Hebrew University Medical School Ein Kerem Jerusalem, 91120 ISRAEL.
Shufaro
Yoel
Y
IVF Unit, The Department of OB/GYN The Hadassah Human Embryonic Stem Cell Research Center Hadassah Hebrew University Medical Center Jerusalem, 91120 ISRAEL.
Gerson
Ariela
A
Departments of Experimental Medicine and Cellular Biochemistry Hebrew University Medical School Ein Kerem Jerusalem, 91120 ISRAEL.
Ueda
Jun
J
Experimental Research Center for Infectious Disease Institute for Virus Research Kyoto University Sakyo-Ku, Kyoto 606-8507 JAPAN.
Deplus
Rachel
R
Laboratory of Cancer Epigenetics Faculty of Medicine Free University of Brussels Brussels 1070 BELGIUM.
Fuks
François
F
Laboratory of Cancer Epigenetics Faculty of Medicine Free University of Brussels Brussels 1070 BELGIUM.
Shinkai
Yoichi
Y
Experimental Research Center for Infectious Disease Institute for Virus Research Kyoto University Sakyo-Ku, Kyoto 606-8507 JAPAN.
Cedar
Howard
H
Departments of Experimental Medicine and Cellular Biochemistry Hebrew University Medical School Ein Kerem Jerusalem, 91120 ISRAEL.
Bergman
Yehudit
Y
Departments of Experimental Medicine and Cellular Biochemistry Hebrew University Medical School Ein Kerem Jerusalem, 91120 ISRAEL.
D000818:Animals; D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004622:Embryo, Mammalian / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011496:Protein Methyltransferases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D000097584:DNA Methyltransferase 3B
D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D050814:Octamer Transcription Factor-3; D011496:Protein Methyltransferases; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C494174:Pou5f1 protein, mouse